PROJECT SUMMARY/ABSTRACT Candidate: The candidate's long-term goal is to establish an independent research program focusing on the neural mechanisms of long-term perceptual plasticity in the auditory system. Her previous training has provided her with a strong foundation in auditory physiology, sensory plasticity, and behavioral neuroscience. Here, she proposes to expand her skill set with additional training in awake-behaving physiology, adeno- associated virus (AAV)-mediated, cell-type specific opsin expression, and wireless optogenetic manipulation of neural activity in awake-behaving animals. During the K99 phase, she will prepare for the transition to independence by attending workshops on chalk talks, teaching practices, job interviews, negotiation, and lab management. By the end of the mentored phase, the candidate will have the academic and practical skills needed to transition to establish her own laboratory. By the completion of the R00 period of this award, she will have the publication record and preliminary data needed to generate a highly competitive R01 application. Environment: K99 phase training will take place at New York University's (NYU) Center for Neural Science, an outstanding environment for postdoctoral level training in systems-level neuroscience. Dr. Dan Sanes, the primary mentor for this application, has an established auditory neuroscience research program that uses a range of approaches, including in vitro slice physiology, in vivo awake-behaving physiology, calcium imaging, psychophysics, and more recently, optogenetics. A collaboration with Dr. Gordon Fishell, located at NYU's School of Medicine, has provided the Sanes Lab with AAV vectors, allowing for targeted, cell-type specific opsin expression. Dr. Fishell has provided a letter of support, indicating his willingness to continue this collaboration, both with Dr. Sanes during the K99 phase of this award, and with the candidate directly, once she achieves independence. Additional mentoring will be provided by Dr. Daniel Polley (Harvard), and Dr. Jonathan Fritz (University of Maryland), both leaders in the auditory neuroscience community. Research: Long-term improvement in sound detection, a process known as perceptual learning, is critical to language acquisition and musical training. Despite its importance, our understanding of the neural mechanisms underlying perceptual learning remains limited. Furthermore, evidence suggests that top-down modulations of cortical activity related to active listening are involved in perceptual learning, but it is unknown whether a causal relationship exists between these processes. The proposed research will address these issues. Wireless recordings will be made from the auditory cortex of animals as they are trained on a sound detection task, revealing the temporal relationship between neural and behavioral improvement as animals learn (K99). Similar recordings from frontal cortex (R00) will establish the dynamics of top-down activity during perceptual training. Wireless optogenetic activation of local inhibitory circuits within auditory cortex (K99) and frontal cortex (R00) will reveal the causal roles of these brain regions in perceptual learning.